Elsevier

Atherosclerosis

Volume 166, Issue 2, February 2003, Pages 387-394
Atherosclerosis

Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes

https://doi.org/10.1016/S0021-9150(02)00371-4Get rights and content

Abstract

Objective: To investigate the relationship of inflammation and endothelial activation with insulin resistance and adiposity in type 2 diabetes. Methods and results: Hundred and thirty-four (45 female) type 2 diabetic subjects aged 50–75 in the Fenofibrate Intervention and Event Lowering in Diabetes Study in Helsinki were examined before fenofibrate intervention. Fasting levels of circulating intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) (vascular cell adhesion molecule), ultra-sensitive C-reactive protein (CRP), human serum amyloid A (hSAA), interleukin-6 (IL-6), macrophage colony-stimulating factor (M-CSF), secretory phospholipase A2 IIA (PLA2), total, HDL and LDL cholesterol, triglycerides, P-glucose, HbA1c, and serum free insulin were determined. Insulin resistance was assessed by the homeostasis model. HOMA IR correlated significantly with all measures of adiposity and markers of inflammation and endothelial dysfunction. BMI was significantly associated with inflammation and endothelial activation, but with neither lipoproteins nor glycaemic control. After controlling for age, gender and BMI, HbA1c correlated significantly with CRP, hSAA, ICAM-1, E-selectin, and HOMA IR. HDL cholesterol correlated inversely with IL-6, M-CSF, E-selectin, and HOMA IR. HbA1c, phospholipase A2, VCAM-1, and HDL cholesterol remained independent determinants of HOMA IR in the linear regression analysis controlled for age, gender, and BMI. Conclusion: Endothelial activation and acute-phase reaction correlate with insulin resistance and obesity in type 2 diabetic patients.

Introduction

Low-grade inflammation is one of the novel risk factors implicated in the development of atherosclerosis [1]. High-sensitivity C-reactive protein has been demonstrated to be associated with insulin resistance and cardiovascular disease (CVD), and proposed to be a useful clinical marker of CVD risk [2], [3]. The major cytokine mediator of the hepatic acute-phase reaction is interleukin-6 (IL-6), which has been argued to play a central role in the pathogenesis of CVD in the insulin resistance syndrome [4].

Another acute-phase reactant associated with CVD risk and insulin resistance is human serum amyloid A (hSAA) [5]. During inflammatory conditions, hSAA is expressed simultaneously with secretory nonpancreatic phospholipase A2 type IIA (sPLA2), associates with HDL producing ‘ acute-phase HDL’ which, paradoxically, enhances sPLA2 activity [5]. In the arterial wall, sPLA2 is expressed by smooth muscle cells [6] and in atherosclerotic lesions, where the amount of sPLA2 correlates with the severity of lesions [7]. There is also evidence that sPLA2 depletes the phospholipid surface of LDL rendering it smaller and denser [6]. Furthermore, circulating levels of sPLA2 are reported to correlate and to predict the occurrence of CVD events [8].

At early stages of atherosclerosis and inflammation, monocytes adhere to the endothelium and infiltrate the vessel wall, activate the vascular endothelium and differentiate into macrophages stimulated by macrophage colony-stimulating factor (M-CSF). M-CSF is produced by monocytes and macrophages, endothelial cells and fibroblasts [9]. Before transformation into macrophages and foam cells, monocytes bind to the activated vascular endothelium due to interaction with selectins and cellular adhesion molecules (CAM), including intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) [10]. During endothelial activation, soluble forms of CAM are shed in the circulation. Increased levels of CAM have been detected in patients with CVD [10], type 2 diabetes [11], and insulin resistance [12]. In addition they have predicted cardiovascular events in type 2 diabetic patients [13]. So far no study has evaluated an overall interplay of these parameters in healthy subjects or in type 2 diabetes.

The purpose of our study is to further evaluate the aetiologic factors for the excess atherosclerosis in patients with type 2 diabetes. We investigated the relationships between inflammation, endothelial activation, and plasma lipids, and the metabolic derangement and insulin resistance in type 2 diabetic patients.

Section snippets

Material

Study subjects were recruited among type 2 diabetic patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study in Helsinki. The FIELD Study is a multinational study ongoing since 1998 in Australia, New Zealand and Finland. Altogether over 9000 type 2 diabetic patients have been randomly assigned to receive either placebo or micronized fenofibrate (200 mg/d) for 5 years. Type 2 diabetic subjects aged 50–75 years and S-cholesterol (S-chol) values between

Results

The clinical and biochemical characteristics of the study subjects are presented in Table 1 and Table 2. Two thirds of the subjects were men (n=89) and one third women (n=45). The glycaemic control of the study subjects was variable with mean glucose and HbA1c values averaging 7.9 mmol/l and 7.1%, respectively.

Conclusions

To the best of our knowledge, this study is the first to investigate the relationship of insulin resistance and several markers of both endothelial activation and low-grade inflammation simultaneously in a type 2 diabetic cohort. Our data suggest a possible link between inflammatory markers–ultrasensitive CRP, IL-6, sPLA2 and hSAA—and insulin resistance as well as adiposity, in middle-aged and elderly men and women with type 2 diabetes. Likewise endothelial activation, i.e. levels of soluble

Acknowledgements

This work was supported by grants from the Finnish Diabetes Association, the Helsinki University Central Hospital, the Swedish Medical Research Council (projects No. 1219 and 13488), the Swedish Heart and Lung Foundation (project No. 41224), and AstraZeneca R&D, Mölndal, Sweden.

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